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Physostigmine is a carbamate that reversibly inhibits cholinesterases in both the peripheral nervous system and the central nervous system (CNS).45 The tertiary amine structure of physostigmine permits CNS penetration and differentiates it from neostigmine and pyridostigmine, from the quaternary amines that have limited ability to enter the CNS. The inhibition of cholinesterases prevents the metabolism of acetylcholine, allowing acetylcholine to accumulate and antagonize the anticholinergic effects of xenobiotics such as atropine, scopolamine,53 and diphenhydramine. Although physostigmine previously was used as an antagonist to the anticholinergic effects of the cyclic antidepressants and the phenothiazines, this use is no longer recommended because of a poor risk-to-benefit ratio given the potential for exacerbation of life-threatening cardiotoxicity. A review of 30 years of the literature reassessed and questioned the contraindication to physostigmine use for cyclic antidepressant ingestions. The review concluded that the safety of physostigmine use for seizures or cardiotoxicity was difficult to predict, but the author still did not recommend physostigmine use in the setting of cyclic antidepressant toxicity.44 Similarly, physostigmine has a poor risk-to-benefit ratio in the management of presumed γ-hydroxybutyrate (GHB) toxicity.47,54 A study in rats given GHB revealed that physostigmine did not effect arousal but increased the risk of physostigmine-induced toxicities of fasciculations and seizures.4

Atypical antipsychotics have complex pharmacologic effects. Although some atypical antipsychotics such as olanzapine have significant antimuscarinic side effects, the benefit of treating these anticholinergic effects with physostigmine in the often confusing overdose setting must be weighed against the potential risks of exacerbating cardiotoxicity.46,52

The history of physostigmine dates to antiquity and the Efik people of Old Calabar in Nigeria.17,20,23,45 The chiefs in this area used a poisonous concoction made from the beans of an aquatic leguminous perennial plant found in the area to deliver the esere ordeal. Esere was the word used to represent both the bean and the ritual used to test the innocence or guilt of an accused person. They also believed that the esere had the power to detect and kill those persons practicing witchcraft. Supposedly, innocent persons quickly swallowed the poison, which caused immediate emesis.23 Vomiting allowed them to survive without therapy or to be given an antidote of excrement in water. The guilty, however, hesitated swallowing, leading to speculation that sublingual absorption led to severe systemic symptoms without the benefit of vomiting. These persons were noted to develop mouth fasciculations and died foaming at the mouth. Daniell, a British medical officer stationed in Calabar, brought samples of the bean and the plant back to England in 1840.23 John Balfour, a professor of medicine and botany at the Edinburgh Medical School, is credited with characterizing the plant, which became known as Physostigma venenosum Balfour (family Leguminoseae) in 1857. The active alkaloid was isolated by Jobst and Hesse in 1864 and was named physostigmine. Independently, one year later Vee and Leven also isolated the active alkaloid ...